Wilms' tumor (WT), a childhood kidney neoplasm, occurs both sporadically and in families. Only a few genes are thought to be important in the etiology of WT, making it an ideal model for studying the role of somatic and germinal mutations in human cancer. Two genes, one an unmapped familial predisposition gene and the other a recently isolated chromosome 11p13 gene (WT1), are known to play a critical role in the development of WT. However, the extent to which mutations at any one locus are important for tumorigenesis is unknown. The goal of Project 9 is to define the role of germinal and somatic mutations at the WT1 locus in WT and WT-associated genitourinary (GU) anomalies and to localize the familial WT predisposition gene. This will be accomplished l) by analyzing WT cases for mutations at the WT1 locus, 2) by characterizing those WT1 mutations, and 3) by genetic linkage analysis of WT families. Patient DNA samples will be screened for somatic and germinal large genetic rearrangements, microdeletions, and point mutations. Detected mutations will be sequenced and further characterized with regard to the intragenic location and type of mutation (deletion or point mutation, transition or transversion, missense or nonsense, absent or altered protein product, dominant or recessive) and the parental origin of the mutant allele. To localize the familial predisposition gene, DNA from individuals from WT families will be analyzed for genetic linkage of the disease phenotype with polymorphic markers throughout the genome. These data will indicate l) how important mutations at the WT1 gene are in WT cases overall and also in WT-related GU anomalies, 2) the location, type, and parental origin of WT1 mutations, 3) the relationship between the type and location of WT1 mutations and the observed phenotypes, and 4) the location of the familial WT gene. These data will then set the stage to understanding the relationship, if any, between these two WT genes, thereby elucidating at the molecular genetic level the mechanism by which two genes act, either independently or in concert, to abrogate normal control of cellular growth and differentiation.